Tuberculosis (TB) and HIV have been closely linked since the emergence of AIDS. Worldwide, TB is the most common opportunistic infection affecting HIV-seropositive individuals,(1) and it remains the most common cause of death in patients with AIDS.(2) HIV infection has contributed to a significant increase in the worldwide incidence of TB.(1, 3) By producing a progressive decline in cell-mediated immunity, HIV alters the pathogenesis of TB, greatly increasing the risk of disease from TB in HIV-coinfected individuals and leading to more frequent extrapulmonary involvement, atypical radiographic manifestations, and paucibacillary disease, which can impede timely diagnosis. Although HIV-related TB is both treatable and preventable, incidence continues to climb in developing nations wherein HIV infection and TB are endemic and resources are limited. Interactions between HIV and TB medications, overlapping medication toxicities, and immune reconstitution inflammatory syndrome (IRIS) complicate the cotreatment of HIV and TB. This chapter will review the epidemiology, pathogenesis, management, and prevention of TB in the setting of HIV infection.

Epidemiology of HIV-Related Tuberculosis

The World Health Organization (WHO) estimates that one third of the world's population is infected with Mycobacterium tuberculosis, resulting in an estimated nearly 9 million new cases of active TB in 2010. Worldwide, 14.8% of TB patients have HIV coinfection, and as many as 50-80% have HIV coinfection in parts of sub-Saharan Africa (Figure
1).(4) The incidence of TB associated with HIV is believed to have peaked at 1.39 million in 2005 and is now decreasing.(5) However, globally, TB remains the most common cause of death among patients with AIDS, killing 1 of 3 patients.(2, 6) After decades of steady decline, the number of TB cases in the United States increased in the mid-1980s.(7)

Between 1985 and 1990, TB cases increased by 20%, resulting in 28,040 excess cases of TB. The U.S. Centers for Disease Control and Prevention (CDC) estimates that AIDS-related TB accounted for a minimum of 30% of these excess cases.(8) Fortunately, TB cases have been declining in the United States since 1992.(9) By 2010, the number of TB cases in the United States had declined to a total of 11,181, a rate of 3.6 cases per 100,000 population, the lowest rate since TB reporting began in 1952.(10)

Among TB-infected individuals in the United States with known HIV test results, 8.6% were HIV coinfected. Foreign-born individuals and members of ethnic/racial minority groups remain disproportionately affected by TB in the United States (Figure
2).(10) Sixty percent of TB cases occurred in foreign-born persons, and TB rates among Hispanic, black, and Asian Americans were 7, 8, and 25 times, respectively, greater than rates for white Americans. Nearly half of TB cases in the United States occurred in the states of California, Florida, New York, and Texas.

The decline in HIV-related TB in the United States and other industrialized countries has paralleled an overall decline in TB cases. Increasing data demonstrate that antiretroviral therapy (ART) is effective in reducing the risk of TB, even in persons with higher CD4 cell counts. The CIPRA HT001 study demonstrated that starting ART at a CD4 count of 200-350 cells/µL compared with waiting until the CD4 count is <200 cells/µL reduced the risk of active TB by 50%.(11) Similarly, the HPTN 052 study found that initiation of ART at a CD4 count of ≥350 cells/µL vs waiting until the CD4 count dropped to <250 cells/µL, was associated with a 47% reduction in the risk of active TB.(12) A metaanalysis of the protective effect of ART on the development of TB demonstrated a 65% risk reduction in TB incidence across all CD4 cell counts. A substantial reduction of 57% was seen in persons with CD4 counts of >350 cells/µL, and the greatest impact was seen in those with CD4 counts of <200 cells/µL: an 84% reduction in TB incidence.(13)

Drug-Resistant Tuberculosis in U.S. and Non-U.S. Settings

Paralleling the increase in TB cases in the United States was an increase in the number of cases of drug-resistant TB. The frequency of multidrug-resistant TB (MDRTB) in the United States increased from 0.4% in the early 1980s to 3.5% in 1991, with most of the MDRTB cases residing in New York.(14) The CDC investigated at least 8 MDRTB outbreaks that occurred in New York, New Jersey, and Miami, and reported that approximately 90% of the cases were HIV seropositive.(15) In New York, previously treated patients, those with HIV infection, and injection drug users were all at increased risk of having drug-resistant TB.(16) HIV infection increases individuals' susceptibility to TB infection and reinfection, including with drug-resistant strains and, additionally, HIV infection may predispose TB patients to acquisition of rifampin resistance through gastrointestinal malabsorption of TB medications.(17)

Since 1997, the MDRTB rate in the United States has declined to about 1% and has remained stable. In 2010, the rate of MDRTB was 1.3%, and the majority of cases (89.4%) occurred in foreign-born individuals.(4) In contrast, in resource-limited settings outside the United States, MDRTB and extensively drug-resistant TB (XDRTB) are a growing problem, with MDRTB estimated to represent 5% of TB cases globally (18) and up to 18-26% of newly diagnosed TB cases in some countries. Drug-resistant TB can be particularly lethal in patients with untreated HIV, with mortality rates as high as 98% in one series.(19) Prompt identification of resistant TB, initiation of effective TB treatment, and early initiation of ART reduce the mortality attributable to drug-resistant TB in HIV coinfection.(20)

Impact of HIV Infection on the Pathogenesis of Tuberculosis

TB can develop through progression of recently acquired infection (primary disease), reactivation of latent infection, or exogenous reinfection. Infection with M tuberculosis can occur when an individual exposed to an infectious case of TB inhales particles (<5 µm in size) containing the tubercle bacilli.(21) If the bacilli reach the pulmonary alveoli, they may be ingested by alveolar macrophages, the first line of defense against M tuberculosis. Surviving tubercle bacilli multiply within the macrophage and eventually undergo hematogenous spread to other areas of the body. In HIV infection, defective macrophages function in response to TB infection, which may in part increase susceptibility to TB disease.(22) Despite this, there is no conclusive evidence that HIV-seropositive persons are more likely to acquire TB infection than HIV-seronegative individuals, given the same degree of exposure.(23, 24)

Once infection does occur, however, the risk of rapid progression is much greater among persons with HIV infection, because HIV impairs the host's ability to contain new TB infection. Immunocompetent individuals infected with M tuberculosis have approximately a 10% lifetime risk of developing TB,(25) with half of the risk occurring in the first 1-2 years after infection. In contrast, HIV-infected individuals with latent TB are approximately 20-30 times more likely to develop TB disease than those who are HIV uninfected, at a rate of 8-10% per year.(4) HIV coinfection also increases the risk of progression of recently acquired infection to active disease.(24) In several outbreak settings, 35-40% of HIV-infected patients exposed to TB in health care or residential settings developed active TB disease within 60-100 days of exposure.(26, 27)

Infection with M tuberculosis in an immunocompetent person is thought to confer significant protective immunity against exogenous reinfection.(25) However, reinfection has been reported in both HIV-seronegative (28, 29) and HIV-seropositive individuals,(30, 31, 32, 33, 34) although its incidence is not known. DNA fingerprinting on paired isolates of M tuberculosis from 17 patients who repeatedly had positive cultures at a single hospital in New York City found 4 patients to have acquired a new, drug-resistant strain of M tuberculosis through exogenous reinfection, probably as a result of nosocomial transmission.(30)

TB can occur early in the course of HIV infection and throughout all stages of HIV infection. The risk of TB increases soon after infection with HIV; in a South African study of gold miners, the risk of TB doubled during the first year after HIV seroconversion.(35) Although TB can be a relatively early manifestation of HIV infection, it is important to note that the risk of developing TB, and of disseminated infection, increases as the CD4 cell count decreases. Even with effective immune reconstitution with ART, the risk of TB generally remains elevated in HIV-infected patients above the background risk of the general population, even at high CD4 cell counts.(36, 37, 38)

The presentation of TB also is affected by the extent of HIV-related immunosuppression. In patients with CD4 counts of >350 cells/µL, the clinical and radiographic presentation is similar to that of patients without HIV infection. However, as immunosuppression advances, the radiographic presentation becomes less typical and extrapulmonary and disseminated disease become more common. In several studies of HIV-infected patients with pulmonary TB, the median CD4 count was >300 cells/µL.(39) However, in patients with primarily extrapulmonary involvement or disseminated disease, the CD4 cell count may be much lower.

Impact of Tuberculosis on the Natural History of HIV Infection

TB may similarly negatively impact the natural history of HIV infection. Several studies have indicated that TB coinfection increases the risk of HIV progression and death, particularly in persons with untreated HIV disease.(40, 41) The effect of TB on HIV disease progression is hypothesized to be attributable to increased immune activation (42) and increased expression of the CCR5 and CXCR4 coreceptors on CD4 cells.(43) Whether TB affects HIV RNA level is less clear. Some studies have found elevated HIV RNA levels in TB-coinfected patients,(44, 45) postulated to be attributable to activation of latent HIV in macrophages as well as to dysregulated cytokines.(46) However, one study has reported lower HIV RNA levels in TB-coinfected patients,(47) and in vitro data suggest an inhibitory effect on HIV replication in macrophages.(48)

Clinical Presentation and Diagnosis

Clinical Presentation of Tuberculosis

The clinical presentation of pulmonary TB can vary widely in both immunocompetent and immunocompromised hosts. In general, the presentation in HIV-infected patients is similar to that seen in HIV-uninfected patients, although the signs and symptoms (such as fevers, weight loss, and malaise) may be attributed to HIV itself and the possibility of TB overlooked. Symptoms usually are present for weeks to months, and an acute onset of fever and cough is more suggestive of a nonmycobacterial pulmonary process. In HIV-infected patients, clinical manifestations of pulmonary TB reflect different levels of immunosuppression. Earlier in the course of HIV disease, TB is more likely to present as classic reactivation-type disease, whereas patients with advanced immunosuppression are more likely to present with findings consistent with primary TB (see Radiographic Findings, below).

The prevalence of extrapulmonary TB and disseminated TB are both increased in HIV-infected patients. Low CD4 cell counts are associated with an increased frequency of extrapulmonary TB, positive mycobacterial blood cultures, and atypical chest radiographic findings, reflecting an inability of the impaired immune response to contain infection.(49) Patients with extrapulmonary TB may present with signs and symptoms specific to the involved site, such as lymphadenopathy, headache, meningismus, pyuria, abscess formation, back pain, and abdominal pain. These findings in HIV-infected patients can present a diagnostic challenge. Whenever possible, diagnostic specimens should be examined for acid-fast bacilli (AFB) and cultured for mycobacteria.

Radiographic Findings

The chest radiograph is the cornerstone of diagnosis for pulmonary TB. Upper-lobe infiltrates and cavities are the typical findings in reactivation TB, whereas intrathoracic lymphadenopathy and lower-lobe disease are seen in primary TB. In HIV-infected persons with higher CD4 counts (ie, >200 cells/µL), the radiographic pattern tends to be one of reactivation disease with upper-lobe infiltrates with or without cavities.(50) In HIV-infected persons who have a greater degree of immunosuppression (ie, CD4 count <200 cells/µL), a pattern of primary disease with intrathoracic lymphadenopathy and lower-lobe infiltrates is seen. As chest radiographs may appear normal in up to 21% of those with culture-positive TB and CD4 counts of <50 cells/µL,(51) a high index of suspicion must be maintained in evaluating an HIV-infected patient with symptoms suggestive of TB.(52, 53)

Diagnosis

Making a diagnosis of TB in HIV-infected individuals can be challenging. HIV patients have higher rates of sputum smear-negative disease. Smear-negative, culture-positive TB is more common and occurs more frequently with advanced immunosuppression. Rates of AFB smear-negative disease vary widely but have been reported as high as 66%.(54) In general, the rate of smear positivity correlates with the extent of radiographic disease. For example, patients with cavitary lesions caused by active TB will more commonly have positive smear results, whereas a negative smear result in a patient with minimal disease on chest radiograph would not be unusual, and would not rule out active TB. However, in HIV-infected patients, positive smear results may be seen with relatively little radiographic evidence. Diagnosis of TB in HIV infection also is made more difficult by the higher rates of extrapulmonary disease and the need to distinguish TB from other infectious and neoplastic complications of HIV.

Symptom Screening

Symptom-based screening tools are of limited utility in establishing a diagnosis of TB in HIV-infected individuals, given the many infectious complications of HIV that can cause symptoms and the diverse manifestations of TB disease in HIV-infected patients. In one study, the presence of cough of any duration, fever of any duration, or night sweats lasting 3 or more weeks in the preceding 4 weeks was 93% sensitive for TB, but only 36% specific.(55) However, use of a targeted symptom screen may help to exclude the diagnosis of TB in HIV-infected patients who are initiating ART or isoniazid (INH) treatment for latent TB infection. One metaanalysis demonstrated that absence of fever, night sweats, weight loss, and cough of any duration had a 97.7% negative predictive value to exclude active TB infection.(56) However, asymptomatic subclinical TB infection has been described, particularly in locations with a high prevalence of TB (57, 58); this would be missed with a symptom screen alone.

Sputum Smear and Culture

It is recommended that at least 2 sputum samples be collected for AFB smear and culture in persons with suspected pulmonary TB. The incremental yield of a third sputum for AFB smear is limited, as low as 2% in one study.(59) Given the high rates of AFB smear-negative disease, culture can be essential to confirm the diagnosis of HIV. In one series, use of 1 broth-based Mycobacteria Growth Indicator Tube (MGIT) culture identified 71% of TB cases, and use of 3 MGIT cultures had the highest yield of strategies evaluated, identifying 98% of TB cases. In terms of incremental yield, a second MGIT culture identified 17% more TB cases, whereas the third MGIT culture had yielded 10% more cases than the second culture.(59) When expectorated sputum specimens are AFB smear negative, further evaluation may be indicated. Bronchoscopy with bronchoalveolar lavage and transbronchial biopsy may be useful in the evaluation of persons with abnormal chest radiograph imagery when sputum smear results are negative. In this setting, a rapid presumptive diagnosis of TB, based on histology and AFB smear of specimens obtained by bronchoscopy, can be made in 30-40% of individuals; that is similar to the yield of bronchoscopy in HIV-uninfected cases with smear-negative pulmonary TB.(60)

Positive cultures for M tuberculosis provide a definitive diagnosis of TB. However, approximately 15% of reported TB cases are culture negative (58); no data are available for HIV-infected cases.

Diagnosis of Extrapulmonary Disease

Testing of specimens from extrapulmonary sites is required to establish a bacteriologic diagnosis of disseminated or extrapulmonary TB. HIV patients with extrapulmonary symptoms or signs of TB should have samples taken from the appropriate anatomic site(s) to increase the likelihood of TB diagnosis. Lymph node biopsy with AFB culture yielded a 42% rate of culture-confirmed TB in one series of HIV/TB-coinfected subjects.(59) Blood culture also may be high-yield in patients with CD4 counts of <100 cells/µL, with a rate of 49% blood culture positivity in one series.(61)

Rapid Testing for TB

Nucleic acid amplification (NAA) tests detect nucleic acid sequences unique to organisms in the M tuberculosis complex, allowing for a rapid diagnosis. Only 1 NAA test is approved currently by the U.S. Food and Drug Administration (FDA), the Amplified Mycobacterium Tuberculosis Direct Test (MTD; Gen-Probe), for use in respiratory specimens from patients who have not been treated previously for TB. The MTD test is approved for use in smear-positive or smear-negative samples. In 2009, the CDC published a suggested algorithm for use and interpretation of NAA test results.(62) These guidelines recommend NAA testing on "at least one respiratory specimen from each patient with signs and symptoms of pulmonary TB for whom a diagnosis of TB is being considered but has not yet been established, and for whom the test result would alter case management or TB control activities." Despite that recommendation for the widespread use of NAA testing in the evaluation of suspected TB cases in the United States, access to the testing often is limited by cost, availability, and local TB control agencies, which frequently restrict use to smear-positive specimens. NAA tests are an important addition to our armamentarium of diagnostic tools, but they do not replace AFB smear, culture, or, more importantly, clinical judgment.

Other rapid TB tests available outside the United States include line probe assays, XPert MTB/RIF, and urinary lipoarabinomannan (LAM). The Xpert MTB/RIF has been of particular interest, as it identifies the presence or absence of TB as well as the presence of rifampin resistance, which is a proxy for MDRTB, within 2 hours. The Xpert MTB/RIF is a self-contained polymerase chain reaction (PCR) platform that requires minimal technical expertise and allows for evaluation of sputum that has been processed (ie, after digestion, decontamination), and some extrapulmonary specimens.(63) In TB-endemic settings, the Xpert MTB/RIF assay's sensitivity in testing a single sputum sample is approximately 98% for AFB smear-positive specimens and 72-75% for AFB smear-negative specimens, with a specificity of 98%.(64, 65) The sensitivity of Xpert MTB/RIF in AFB smear-negative patients increased to 90% with testing of 3 sputum samples.(64) Data vary on the impact of HIV on the test performance of Xpert MTB/RIF; HIV infection is associated with more smear-negative and paucibacillary disease, and the Xpert MTB/RIF is less sensitive with smear-negative samples. Of concern, some studies have indicated a trend toward reduced sensitivity in HIV-infected, AFB smear-positive patients(66); this requires further evaluation. Xpert MTB/RIF currently is not approved by the FDA.

Urinary LAM testing is a true point-of-care test, with a lateral-flow dipstick that can be dipped in patient urine, and it requires minimal technical expertise to process. LAM testing appears to perform better in patients with HIV infection than in those without HIV, particularly in those with CD4 counts of <50 cells/µL,(67) which in part may be attributable to the higher rates of disseminated TB in that population. The overall sensitivity of urinary LAM testing in culture-positive TB patients with HIV infection is low (40-60%),(67) but increases to 67-85% in those with CD4 counts of <50 cells/µL.(68, 69) Specificity has been reported as 99-100% in HIV infection. Given its limited sensitivity, urine LAM has been proposed as a "rule in" test but appears inadequate as a stand-alone "rule out" test for TB.

Treatment of HIV-Related Tuberculosis

Successful treatment for drug-sensitive TB generally requires 6 months of therapy. The first 2 months of treatment is often referred to as the intensive phase, and typically entails the use of 4 drugs--rifampin (or other rifamycin), INH, pyrazinamide, and ethambutol--followed by 4 months (called the continuation phase) with rifampin and INH alone (see Table
1). Treatment duration is extended to 9 months for patients with cavitary disease at baseline, those with a positive culture after 2 months of treatment, and those who did not receive pyrazinamide during the first 2 months.(70) Patients with evidence of drug resistance require a modified regimen and, often, a more-lengthy course of treatment.

HIV-infected patients with TB generally respond well to anti-TB therapy, as long as the regimen contains INH and a rifamycin for the duration of TB treatment. As for HIV-uninfected individuals, the standard recommendation for HIV-coinfected individuals with pulmonary TB is a 6-month course of treatment, with extension to 9 months for patients with cavitary lung disease and culture positivity at 2 months of TB treatment.(71) A 2010 metaanalysis found a trend toward increased risk of relapse with 6 months of TB treatment compared with ≥8 months of treatment.(72) However, most of the studies included in the metaanalysis were not randomized and most did not distinguish reinfection from relapse. Randomized trials will be needed to establish whether ≥8 months of treatment is indeed more efficacious than 6 months in HIV/TB coinfection. Longer courses of TB treatment are required for central nervous system (CNS) TB and for drug-resistant TB.

The 2010 metaanalysis examined the efficacy of daily versus thrice-weekly dosing of TB medications and found that, in a pooled analysis, daily dosing during the continuation phase of TB treatment was associated with improved TB outcomes (72); studies directly comparing daily with thrice-weekly TB treatment have not been completed but are under way.(73) The WHO currently recommends daily administration of TB treatment at least for the intensive phase of therapy in persons with HIV coinfection.(74) Administration of ART is recommended during TB therapy regardless of the CD4 cell count,(74) because ART is associated with reduction in mortality and HIV disease progression. Timing of ART initiation during TB therapy is addressed below. All HIV-infected patients with active TB should receive trimethoprim-sulfamethoxazole prophylaxis.(75, 76)

Safety and Tolerability

The risk of adverse reactions to TB treatment is higher in HIV-infected individuals than in HIV-uninfected individuals, occurring in approximately 25% and 13%, respectively.(77) Hepatotoxicity is common in the treatment of TB in HIV-infected patients, and may be exacerbated by overlapping toxicities with antiretroviral (ARV) and antibiotic medications such as fluconazole and trimethoprim-sulfamethoxazole, by coinfection with viral hepatitis, or by preexisting liver disease.(78, 79)

Thiacetazone, which is used in many developing countries for the treatment of TB, has been reported to cause frequent and significant skin reactions in HIV-infected patients being treated for TB.(80, 81) In one study, up to 20% of the HIV-seropositive patients on thiacetazone developed cutaneous rashes, compared with 1% of the seronegative cases; the case-fatality rate was 14% in the HIV-seropositive persons suffering these reactions.(81) The risk of cutaneous reactions in a randomized trial of thiacetazone- and rifampin-containing regimens was nearly 10 times higher in the HIV-seropositive cases compared with the seronegative cases.(80) These reports prompted the WHO to abandon thiacetazone in the treatment of HIV-related TB.(3)

ART Coadministration with TB treatment: Drug Interactions

There are substantial overlapping drug toxicities and drug-drug interactions that must be considered when cotreating HIV and TB. In particular, the rifamycin derivatives (ie, rifampin, rifabutin, and rifapentine) can induce the hepatic cytochrome P450 enzyme system, resulting in increased metabolism and decreased serum levels of nonnucleoside transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors, and the CCR5 antagonist, as well as other drugs. Many ARVs, in particular NNRTIs and PIs, can affect cytochrome P450 enzymes, resulting in bidirectional drug-drug interaction between many HIV medications and rifamycins. Data are not available for all ARV-TB medications interactions. Drug-drug interactions and recommended dosing are summarized in (Table
2 and Table
3).

Choice of Rifamycin

Rifamycins currently are the cornerstone of effective TB treatment and are recommended for the duration of TB treatment in persons with HIV coinfection. In the HIV-infected population, regimens that do not include a rifamycin in the continuation phase have been associated with a 2-3 times higher risk of recurrence.(72, 82, 83) Rifamycins have significant drug-drug interactions with many ARVs (in particular with PIs, NNRTIs, integrase inhibitors, and the CCR5 antagonist). The most commonly used rifamycin in TB treatment is rifampin, which has substantial drug-drug interactions owing to induction of hepatic metabolism of many other drugs. Only certain ARV agents can be coadministered with rifampin; these are reviewed in more detail below. Rifabutin is another rifamycin that is highly active against M tuberculosis but has less impact on hepatic microsomal metabolism; it therefore has been the drug of choice for coadministration with ARVs that are problematic with rifampin, such as the ritonavir-boosted PIs. It is important to note that, even when rifampin is changed to rifabutin to avoid drug interactions with ARVs, the CYP3A4 enzyme induction from rifampin is estimated take up to 2 weeks to dissipate after discontinuation.(84, 85) Therefore, a change from rifampin to rifabutin will need to be planned in advance of starting an ART regimen that is negatively impacted by rifampin, to avoid subtherapeutic ARV levels. Limited data suggest that rifabutin- and rifampin-based regimens are equally efficacious.(86, 87, 88, 89)

Intermittently dosed rifamycins (eg, administered every other day or weekly) have been associated with relapse of TB and resistance to rifamycins in some studies; this may more be more common in individuals with advanced AIDS and low CD4 cell counts, owing in part to malabsorption and increased bacillary burden in this population.(90, 91, 92) Twice-weekly administration of rifabutin has been associated with relapse and acquired rifamycin resistance. Based on these findings, for HIV-infected persons with CD4 counts of <100 cells/µL, daily therapy is indicated during the first 2 months, followed by either daily or thrice-weekly therapy during the continuation phase.(93, 70) Rifapentine is a potent rifamycin with a long half-life that has been used in intermittent dosing regimens in HIV-uninfected patients. In persons with HIV/TB coinfection, once-weekly rifapentine has been associated with impaired efficacy and acquisition of rifamycin resistance (94) and is not recommended for TB treatment in persons with HIV infection. The efficacy of daily rifapentine currently is under evaluation, but there are no data yet supporting its use in HIV/TB coinfection. Therefore, rifapentine is not recommended for TB treatment in HIV-infected persons except in the context of clinical trials.

Nonnucleoside Reverse Transcriptase Inhibitors

Efavirenz (EFV)-based ART currently is the treatment of choice for patients who are receiving rifampin as part of TB treatment.(95, 74) Rifampin coadministration reduces serum EFV concentrations (area under the curve [AUC] decreased by 22%),(96) raising the question of whether EFV should be increased to 800 mg when given with rifampin, particularly with patients weighing >50 kg. However, EFV levels in the presence of rifampin are quite variable and may be determined in part by the CYP3A4 2B6 alleles of the treated individuals. Patients with a T/T 2B6 polymorphism, which is more common in sub-Saharan African and African American populations than in Europeans (97) and European Americans,(98) experience higher levels of EFV when it is coadministered with rifampin.(99, 100) Higher EFV levels have been associated with CNS toxicity in some studies.(99, 101, 102) In a South African clinical study, there was not a difference in rates of HIV suppression between HIV/TB-coinfected patients given an ART regimen containing EFV 600 mg daily with rifampin and HIV-monoinfected patients given EFV 600 mg daily without rifampin.(103) In comparisons of EFV 600 mg daily with EFV 800 mg daily, both given with rifampin, there were no differences in rates HIV virologic suppression in a Thai study (104) or in a South African study.(105) Several noncomparative observational studies indicate appropriate HIV virologic suppression and clinical outcomes when ART regimens containing EFV 600 mg daily are coadministered with rifampin-containing TB regimens.(106, 107) Collectively, these data suggest that 600 mg of EFV is appropriate for coadministration with rifampin, particularly in black and Asian populations. Whether Caucasian patients weighing >50 kg require a higher dosage of EFV with rifampin has not been evaluated in randomized clinical trials. There are limited data on use of EFV with rifabutin. It is recommended that the rifabutin dosage be increased to 450-600 mg daily when coadministered with EFV because of CYP3A4 enzyme induction by EFV.(95, 108)

Nevirapine concentrations also are reduced by rifampin, with an AUC decrease of 20-50%.(97, 109, 110, 111) When nevirapine was initiated using standard lead-in dosing in the setting of ongoing rifampin-based TB treatment, inferior rates of HIV virologic suppression were observed, compared with EFV, in a South African study,(103) but not in two Thai studies.(112, 113) However, starting nevirapine at a dosage of 400 mg without a lead-in dosing of 200 mg daily is associated with higher rates of nevirapine hypersensitivity, even when patients have been on rifampin for several weeks before nevirapine initiation.(112) When available and not contraindicated, EFV is preferable to nevirapine in the HIV treatment of TB-coinfected patients when an NNRTI is used.

Data on drug interactions of rifampin and rifabutin with the NNRTIs rilpivirine or etravirine are limited. Rifampin decreases serum rilpivirine levels substantially and is anticipated to decrease etravirine levels; therefore, it is not recommended for coadministration with either agent. Rifabutin also decreases rilpivirine concentrations and should not be coadministered. Rifabutin lowers etravirine AUC by 37% and, in turn, etravirine decreases rifabutin concentrations; current recommendations are to dose rifabutin at 300 mg daily when given with etravirine.(95) Rifabutin should NOT be given with etravirine if a concomitant PI is being used, owing to drug-drug interactions.

Protease Inhibitors

Rifampin greatly reduces plasma concentrations of PIs and therefore cannot be coadministered safely with PIs given at standard dosages.(114, 115, 116) Two alternative approaches currently are available for giving rifamycin-based TB treatment with ritonavir-boosted PIs: 1) using rifabutin rather than rifampin; or 2) using rifampin with increased dosages of ritonavir or the PI. Rifabutin has a complex bidirectional drug interaction with PIs, with rifabutin increasing PI levels and PIs increasing rifabutin levels. This has led to a recommendation that the dosage of rifabutin be reduced. The initial dosing recommendation of rifabutin 150 mg every other day may result in inadequate rifabutin concentrations, as several reports have emerged of acquired rifamycin resistance when this dosage of rifabutin is given with ritonavir-boosted PIs.(117, 118) The 2012 U.S. Department of Health and Human Services guidelines recommend giving rifabutin 150 mg daily or 300 mg every other day (95); however, clinical data to support this approach are limited, and the ideal dosage of rifabutin for boosted PI coadministration is still under evaluation. There may be a role for rifabutin therapeutic drug monitoring, where available, in patients treated with a ritonavir-boosted PI and rifabutin. It is essential to recognize that, if the PI is discontinued, the dosage of rifabutin would need to be adjusted upward to a standard dosage of 300 mg daily.

When rifabutin is not available, doubling the dosage of the PI ("double dosing") or the accompanying ritonavir ("super boosting") can restore therapeutic plasma PI levels,(114, 119) but that approach is associated with increased gastrointestinal side effects and hepatotoxicity. If available, alternatives to coadministration of double-dosed, super-boosted PIs with rifampin are preferred.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

Rifamycin-based TB treatment generally does not have significant drug-drug interactions with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and dosage adjustment of NRTIs is not required. INH and the NRTIs zidovudine (ZDV), stavudine (d4T), and didanosine (ddI) all can contribute to peripheral neuropathy, and coadministration particularly of d4T should be avoided, if feasible.(120) Pyridoxine should be given to all HIV-infected patients being treated for active TB, to reduce the risk of INH-associated neuropathy.

Integrase Inhibitors

Rifampin decreases concentrations of the integrase inhibitor raltegravir. Doubling the dosage of raltegravir compensates for decreases in the AUC but does not normalize raltegravir trough levels.(121) It is unclear whether it is necessary to increase raltegravir dosage. Preliminary results of a randomized controlled trial of raltegravir 400 mg twice daily vs 800 mg twice daily in rifampin-treated TB patients (REFLATE) demonstrated equivalent rates of HIV suppression in the two treatment groups, and these were similar to rates of virologic suppression with EFV.(122) However, 4 participants developed integrase inhibitor resistance in the 400 mg BID arm whereas only 1 participant had integrase resistance in the 800 mg BID arm, suggesting that rifampin may jeopardize adequate raltegravir levels when it is given at the standard 400 mg twice-daily dosage. Until more data are available, the conservative approach would be to dose raltegravir at 800 mg twice daily when giving it with rifampin. Elvitegravir is metabolized by CYP3A4 and therefore its serum concentration may be reduced by rifampin; coadministration is not recommended. Dolutegravir concentrations also are decreased by coadministration of rifampin; doubling the dosage of dolutegravir results in plasma concentrations comparable to those seen without rifampin. Given the efficacy of dolutegravir at dosages of <50 mg daily, it is unknown whether this dosage adjustment is necessary.(123)

CCR5 Antagonists and Fusion Inhibitors

The CCR5 antagonist maraviroc (MVC) is metabolized by CYP3A4, and MVC concentrations are reduced by rifampin. Owing to limited clinical data, coadministration of MVC and rifampin is not recommended, but if alternatives are not available, an increase in MVC dosage to 600 mg twice daily may be considered.(124) There are no data for interactions of rifabutin with MVC; MVC levels may be slightly decreased but dosage adjustment currently is not recommended, unless there is another strong CYP3A4 inhibitor or inducer in the regimen. The fusion inhibitor enfuvirtide is not affected by coadministration with rifamycins.

Other HIV-Related Medications Affected by TB Treatment

Rifamycins also interact with several antifungals commonly used for treatment or prevention of opportunistic infections. Coadministration of rifampin with ketoconazole or fluconazole decreases the AUC of the antifungal by approximately 80% and 20%, respectively.(125) Therefore, ketoconazole and rifampin should not be given together. Rifampin and fluconazole can be used together, but the fluconazole dosage may need to be increased.

Initiation of Antiretroviral Therapy in the Coinfected Patient

In HIV-infected persons with TB, ART should be initiated (or continued) during TB treatment regardless of the CD4 cell count. The SAPIT trial, conducted in patients with CD4 counts of ≤500 cells/µL, demonstrated a relative reduction in mortality of 56% for those who started ART during the 6 months of TB treatment compared with those who initiated ART after completion of TB therapy. The reduction in mortality was seen in patients with CD4 counts of ≤200 cells/µL as well as in those with CD4 counts of >200 cells/µL.(126) Timing of ART initiation in relation to TB treatment start has been clarified further by the SAPIT, CAMELIA, and ACTG 5221 STRIDE studies. In patients with CD4 counts of <50 cells/µL, initiation of ART within 2-4 weeks of TB treatment start was associated with a reduction of the combined endpoint of mortality and AIDS progression by 68% in SAPIT and 42% in STRIDE.(107) The CAMELIA study, which enrolled patients with CD4 counts of <200 cells/µL, found a reduction in mortality of 34% with initiation of ART within 2 weeks of TB treatment start in all enrolled patients, regardless of CD4 cell count; however, the median CD4 count was quite low at 25 cells/µL (interquartile range: 11-56 cells/µL).(127) Collectively, these data indicate that ART should be started very shortly after TB treatment initiation in TB patients with advanced HIV disease. In those with higher CD4 cell counts, it may be safe to defer ART for 2-8 weeks after TB start, but ART should not be delayed until after completion of TB treatment. Importantly, early initiation did not impair HIV RNA suppression in these studies.

Decisions about the timing of ART initiation should be made on a case-by-case basis, taking into account the patient's immunologic status as discussed above and factors such as adherence (including motivation and stability of living situation) and potential for complications (eg, clinically active hepatitis C). Involvement of the patient in deciding whether and when to start ART is crucial.

The need for early initiation of ART will necessitate coordination between TB care and HIV care, along with heightened vigilance for drug toxicities, education about adherence to multiple medications, and anticipation of increased rates of immune reconstitution syndrome (see below). Providers may need to start empiric ART while awaiting HIV genotype information.

Optimal timing of ART in patients with CNS TB disease remains unclear. A Vietnamese study of HIV-infected patients with TB meningitis did not find a mortality benefit at 9 months with early (at time of study entry) vs later (2 months after study entry) ART initiation.(128) Mortality in both groups was exceptionally high: 55% and 60%, respectively, 9 months after randomization, with the majority of deaths occurring within the first month. More grade 4 serious adverse events occurred in the earlier ART arm compared with the later arm (80.3% vs 69.1%; p = .04). As TB meningitis can be particularly challenging to diagnose, clinicians must retain a high index of suspicion for it and monitor patients with CNS disease closely, given the poor outcomes associated with this disease.

In patients already receiving ART, HIV treatment should be continued, and modifications to either the TB regimen or the ARV regimen can be made as indicated to avoid drug-drug interactions between ARV and TB medications.

It is important to be aware of the potential problems that can occur when anti-TB medications and ARV agents are administered concurrently. In addition to the drug-drug interactions discussed above, the medications may have overlapping toxicities. Gastrointestinal complaints and rash are not uncommon with anti-TB medications and these also can be quite common with certain ARV medications. A flulike illness has been described with rifampin, which could be confused with an abacavir hypersensitivity reaction. Peripheral neuropathy is an adverse effect of INH as well as the NRTIs d4T and ddI. Elevated liver function test results can occur with INH, rifampin, pyrazinamide, and with most of the NRTIs, NNRTIs, and PIs.

Determining which medication is the offending agent can be challenging. In the setting of TB, this usually involves holding all medications and restarting sequentially to determine which medication caused the problem. Although this approach works quite well with TB medications, in the case of HIV infection, sequential addition of ARV drugs is not advisable because of the risk of developing ARV resistance. When an adverse reaction occurs with ARV medications, the agent most likely to be responsible usually is deduced based on known adverse-effect profiles and clinical judgment.

TB Immune Reconstitution Inflammatory Syndrome

TB immune reconstitution inflammatory syndrome (IRIS) encompasses 2 distinct entities: paradoxical TB IRIS, a clinical deterioration that occurs in a patient already on TB treatment, and unmasking TB IRIS, characterized by a new diagnosis of TB, usually with a robust inflammatory presentation, after the initiation of ART. Paradoxical TB IRIS is a clinical diagnosis, characterized by new or worsening enlarged lymph nodes, radiographic features of TB, serositis, or CNS manifestations, and often, less-specific symptoms such as fever, night sweats, weight loss, and respiratory and abdominal symptoms.(129)

Paradoxical TB IRIS is associated with low CD4 cell count at the time of ART initiation, high HIV RNA levels, and a shorter interval between TB treatment start and ART initiation. TB IRIS most commonly occurs within the first 2-3 months after ART initiation.(130) Paradoxical TB IRIS can occur in the absence of ART initiation; TB IRIS was initially described in HIV-uninfected patients treated for TB and experiencing clinical deterioration after initial improvement.(131)

There is no diagnostic test available for TB IRIS. Patients with suspected TB IRIS should be evaluated for other opportunistic infections, poor adherence or inadequate absorption of TB drugs, and importantly, for drug-resistant TB, which can be clinically indistinguishable and is a significant cause of clinical deterioration in patients on TB treatment in regions where rifampin resistance is a growing problem.(132)

TB IRIS often can be managed symptomatically without specific intervention. Severe TB IRIS may require prednisone to reduce inflammation; ART should be continued without interruption, if possible. A randomized, double-blind controlled trial of prednisone in patients with TB IRIS demonstrated that prednisone reduced the need for hospitalization and procedures.(133) TB IRIS is seldom fatal but it has been attributed to deaths.

Diagnosis and Treatment of Latent Tuberculosis Infection

Diagnosis of Latent Tuberculosis Infection

Screening for latent TB infection (LTBI) is an essential step in controlling the spread of TB. Screening for LTBI is recommended in persons at risk of recent infection and in those groups with increased risk of progression to active disease once infected, including HIV-infected persons. Current CDC and U.S. Department of Health and Human Services guidelines recommend LTBI testing for all newly diagnosed HIV-infected persons. Repeat testing is recommended for patients whose CD4 cell count increases from low numbers to counts of >200 cells/µL, and annual testing is suggested for patients whose initial test result is negative and for those who are considered at high risk of repeated or ongoing exposure to TB (such as individuals who are incarcerated, are active drug users, reside in a congregate setting, or reside in or travel to a TB-endemic setting).

Both the tuberculin skin test (TST or Mantoux method) and interferon-gamma release assays (IGRAs) can be used to test for LTBI. With TST testing, a reaction of ≥5 mm induration is considered positive for HIV-infected patients. Use of the 5 mm cutoff is supported by a prospective study in the United States demonstrating that the risk of TB was significantly higher in HIV-infected persons with TST reactions of ≥5 mm induration than in those who have a reaction of <5 mm.(134)

Unlike TST test results, IGRA results are not interpreted based on risk but are the same for all individuals tested. IGRAs yield 1 of 3 results: positive, negative, or indeterminate. An indeterminate result indicates that the test cannot be interpreted, because of either technical problems with the assay or an insufficient immune response from the blood being tested. IGRAs appear to perform at least as well as TSTs in HIV-infected individuals. Owing to the use of antigens that are more limited to mycobacterial TB, IGRAs are more specific for LTBI infection than TSTs and are not cross-reactive in patients who have been vaccinated with BCG. However, false-positive IGRA results for LTBI have been described.(135) For U.S.-born HIV-infected patients who have high CD4 cell counts on ART and no TB risk factors other than HIV infection, it is reasonable to retest after a positive IGRA result to investigate the possibility of a false positive.

Regardless of TST or IGRA results, HIV-infected individuals with known close contact to an active TB case should be screened for active TB and offered treatment for LTBI if they have no evidence of active TB.

It is important to keep in mind that a negative TST or IGRA result does not exclude infection or active disease. Both tests depend on the presence of an intact cell-mediated immune response. In the setting of HIV infection, reduced cell-mediated immunity can lead to decreased delayed-type hypersensitivity (DTH) responsiveness, resulting in false-negative TST results and false-negative or indeterminate IGRA results. In a multicenter study in the United States, the prevalence of a positive TST result (≥5 mm induration) was shown to decrease with decreasing CD4 cell counts.(136) Similarly, in HIV-infected persons undergoing IGRA testing, indeterminate results occur in approximately 4-7% of patients, and in up to 25% of individuals with CD4 counts of <100 cells/µL.(137, 138) Any symptomatic persons who are at risk of active TB infection (eg, injection drug users, individuals who are incarcerated, or persons who have resided in high-prevalence regions) should have a chest radiograph performed to evaluate for active TB, even if the test result for LTBI is negative, and particularly if their CD4 T-cell count is low. Anergy testing with multiple skin test antigens (eg, Candida, mumps) is no longer recommended.(139)

Treatment of Latent Tuberculosis Infection

HIV-infected individuals with LTBI have a high rate of progression to active TB compared with HIV-uninfected persons. Effective treatment with ART reduces the chance of progression to active TB and is an important preventative intervention.(11, 140) However, even on effective ART, HIV-infected persons still have on average 2 times higher risk of active TB than HIV-uninfected members of their community.(36, 5) Fortunately, treatment of LTBI is very effective in preventing persons infected with M tuberculosis from developing active disease. Screening of all HIV-infected persons for LTBI, and treatment of those coinfected with M tuberculosis, therefore, is recommended. Treatment regimens for LTBI are not adequate for the treatment of active TB. Therefore, after a positive skin test result, the possibility of active TB should be investigated before providing treatment for latent infection.

Current American Thoracic Society/CDC Recommendations for LTBI treatment

The current guidelines from the American Thoracic Society and CDC offer several treatment options for the treatment of LTBI in HIV-infected persons.(141) The preferred option is to give INH daily or twice weekly for 9 months. An INH-containing regimen should be supplemented with pyridoxine (25-50 mg/day) to prevent the development of peripheral neuropathy. Four months of daily rifampin is the alternative treatment for patients who cannot tolerate INH and those who have been exposed to a known INH-resistant index case. Rifabutin can be used in place of rifampin for patients taking ARV medications that cannot be coadministered with rifampin, such as PIs. Although there are no studies of rifabutin-containing regimens in the treatment of LTBI, rifabutin appears to be of equivalent efficacy to rifampin in the treatment of TB. The CDC has endorsed a new shorter-course regimen of once-weekly INH plus rifapentine for a total of 12 weeks, based on a study that demonstrated improved treatment completion and equivalent TB prevention efficacy when compared with 9 months of INH.(142) Like the other rifamycins, rifapentine has substantial drug-drug interactions with some ARV medications and should not be given to HIV-infected patients on ART until further data are available to guide appropriate dosing of ARVs.

A 2-month regimen of rifampin plus pyrazinamide is no longer recommended, owing to unacceptably high rates of hepatoxicity in HIV-uninfected individuals; that regimen should be used with caution, and only with patients who can be closely monitored and for whom the likelihood of completing a longer treatment course is low.

Individuals with known contact with an INH-resistant case should receive rifampin- or rifabutin-based LTBI treatment. Data on optimal regimens for LTBI treatment after known exposure to MDRTB are limited; some experts recommend 2-drug regimens, and consultation with a local TB department is recommended.

Duration of Therapy

The current recommended duration of INH-based LTBI treatment in settings with low TB prevalence is 9 months, instead of the previously recommended duration of 12 months. This recommendation is generalized from data in HIV-uninfected persons indicating that 12 months of INH is more efficacious than 6 months of therapy in preventing active TB but that minimal benefit is gained by extending treatment from 9 to 12 months.(143) In highly TB-endemic settings where reinfection with TB may be common, LTBI treatment of up to 6 years has been well tolerated and has been associated with reduced rates of active TB in patients remaining on therapy.(144, 145) However, longer duration of LTBI treatment also is associated with decreased medication adherence. Defining the settings in which patients may benefit from longer duration of LTBI treatment, even lifelong treatment, is an area of active investigation.

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